Process for the preparation of formyl steroids and products obtained thereby



United States Patent vic, Paris, France, assignors to Les LaboratoiresFraneais de Chimiotherapie, Paris, France, a corporation of France NoDrawing. Filed Dec. 15, 1959, Ser. No. 859,577 Claims priority,application France July 8, 1959 8 Claims. (0. 260397.4)

The present invention involves the preparation of steroids having analdehyde function and, more particularly, it relates to a process forpreparation of 17-formyl androstanes and ZO-formyl pregnanes.

It is known that the formyl steroids are valuable intermediate productsfor the synthesis of steroids. The presence of the forrnyl group in thel7-position of compounds of the androstane series makes it possible totransform them into the corresponding 20-hydroxy pregnanes by a Grignardreaction. The ZO-formyl pregnanes, which are also made by the processaccording to the invention, are useful in preparation of substitutionswhich were heretofore unusual and which modify especially thephysiological properties of the pregnane starting materials. Inaddition, it is possible to prepare by known processes, starting from20-formyl pregnanes, the corresponding l7u-hydroxy-20-keto-pregnanes(see for example US. Patent 2,777,843 to Chemerda, issued January 15,1957).

Prior to the present invention these formyl steroids have, in general,been obtained by the degradation of the lateral chain of cholestanederivatives or of cholane to obtain the ZO-formyl pregnanes, or by totalsynthesis involving the building up of the D-ring starting fromderivatives of phenanthrene to obtain the 17-formyl androstanes.

We have now found, and this is an object of the present invention, thatthe 17-formy1 and ZO-formyl steroids can be prepared starting with thecorresponding keto steroids. Thus, the present invention provides asimple and easy way of obtaining these products which are important forthe synthesis of steroids.

A further ,object of the invention is the preparation of 17-formyl and20-formyl derivatives of steroids of the androstane and pregnane series,starting with the corresponding 17-keto and 20-keto compounds andgoingthrough the intermediate hydroxy-lower alkoxymethyl derivatives.

A still further object of the invention is the preparation of novelhydroxy-lower alkoxymethyl intermediates and 17-formyl and 20-f0rmylderivatives of the androstane and pregnane series such as (a) The3-methyl ether of l7a-methoxymethylestradiol;

(b) The 3-methyl ether of 17u-ethoxymethylestradiol;

(c) 17B-formyl-3-methoxy-A -androstatriene;

(d) The semicarbazone of 17p formyl 3 meth0Xy- A -androstatriene;

(e) 3 3 acetoxy 17}? hydroxy 17a methoxymethyl-A -androstene;

1 I on \If \lfomon (1) 30a acetoxy 20; methoxymethyl 20hydroxypregnane-l l-one.

These and other objects of the invention will become more apparent asthe description proceeds.

The process which is the object of the present invention consistsessentially of treating the 17-keto androstanes or ZO-keto pregnaneswith a lower alkoxymethyl magnesium halide and subjecting the loweralkoxymethyl tertiary steroid alcohols thus obtained to the action ofacid dehydrating agents.

The two stages of the process may be summarized for the two series ofsteroids by the following simplified schematic reaction formulas:

\l -O TOE CHO CHgOR Q] Q 3 lens wherein R represents a lower alkylradical.

An important characteristic of the invention resides in that thereaction of the keto steroids with the organo magnesium compound iscarried out in solution in a cycloalkylene ether.

Another important characteristic resides in that this reaction iscarried out in the presence of a halide of a metal belonging to thesecond group of the periodic table of elements.

It is advantageous to use as the lower alkoxymethyl magnesium halideeither a bromide or a chloride of methoxymethyl magnesium or a bromideor chloride of ethoxymethyl magnesium.

The preferred cycloalkylene etherfor the reaction with the organomagnesium compound is tetrahydrofuran, but 2-methy1 tetrahydrofuran ortetrahydropyran are also suitable. Advantageously, the halide of a metalbelonging to the second group of the periodic table of elements ismercuric chloride; however, a halide of zinc or cadmium may also beemployed.

For the execution of the second stage of the present process of reactingwith an acid dehydrating agent, oxalic acid or phosphorous oxychlorideare preferably used as the acid dehydrating agents, but other reactantsof the same type may be employed without departing from the scope of theinvention.

The invention also relates to the steroid compounds obtained by thepresent process, as well as the intermediates of our preparation, asnovel industrial products.

The schematic flow sheet of Table I shows the formulas of the compoundsdescribed in the exemplary portion. v

The following non-limiting examples will make the invention betterunderstood.

The melting points are instantaneous melting points determined on aMaquenne block. The temperatures are given in C.

EXAMPLE I Preparation of 17B frmyl-3-meth0xy-A -androstatriene (IV) byway of the intermediate 3-methylether of 17ameth0xymethyl-estradiol (II)(a) gm. of the methyl ether of estrone are introduced into 50 cc. oftetrahydrofuran containing 5 gm. of magnesium turnings and 0.2 gm. ofmercuric chloride, the mixture is heated to reflux and then 25 cc. ofmonochlorodimethyl ether, dissolved in 35 cc. of tetrahydrofuran areadded. Refluxing is continued for 1 hour. Thereafter, the reactionmixture is concentrated, poured over ice and acidified by addingconcentrated hydrochloric acid. It is then extracted several times withmethylene chloride. The extract solutions are combined, washed withwater and dried and the solvent is distilled oif. The residue issubjected to chromatography over alumina and eluted with methylenechloride. The first two eluted portions yield 5.16 gm. of the productwhich is again subjected to chromatography over alumina and eluted withbenzene to obtain 2.56 gm. of the 3-methyl ether of17e-methoxymethyl-estradiol (II). For analysis, the product isrecrystallized from ether to obtain a product which melts at 102 C. andhas a specific rotation of [a] =+44 (c.=0.5% in chloroform). It issoluble in alcohol, ether, acetone, benzene and chloroform and insolublein water.

Analysis.-C H O molecular Weight 330.45. Calculated: C, 76.32%; H,9.15%; O, 14.53%. Found: C, 76.3%; H, 9.1%; O, 14.9%.

The infra-red spectrum confirms the indicated structure.

Starting with 4 gm. of compound I, and replacing the chlorodimethylether with bromodimethyl ether, 2.07 gm. of compound II are obtainedwhich is identical to the product described above.

The product is not described in the literature.

(b) 560 mgm. of compound II are heated to 110- 120 C. with 430 mgm. ofoxalic acid containing two molecules of water of hydration. After 1 hourof heating the mixture is cooled and extracted with ether. The extractsolutions are washed with sodium bicarbonate and then with water, driedand the solvent is driven off. The residue, which weighs 450 mgm.,consists of the aldehyde 17B-formyl-3-methoxy-A -androstatriene (IV)which is difiicult to crystallize. The semicarbazone of compound IVmelts at 260 C. with decomposition. The product is very slightly solublein alcohol and chloroform and insoluble in Water and ether.

Analysis of the semicarbazone.--C H O N molecu lar weight: 355.47.Calculated: N, 11.82%. Found: N, 11.4 to 11.6%.

It is not described in the literature. This compound IV is useful as anintermediate in the preparation of l9-nor steroids.

EXAMPLE II Preparation of compound IV by way of the intermediate3-methyl ether of 17a-ethoxymethyl-estradiol (111) 5.14 gm. of themethyl ether of estrone are dissolved by refluxing in 130 cc. oftetrahydrofuran containing 5 .14 gm. of magnesium. Thereafter, 100 mgm.of mercuric chloride are added and then 25 cc. of chloromethylethylether dissolved in 30 cc. of tetrahydrofuran. 'Ihe reaction is rathervigorous; the solvent is allowed to distill off freely, which entrainsthe excess of reactant which is then reintroduced dropwise into thereaction medium. At the end of 45 minutes a crystalline precipitatebegins to form; the distillation is continued under the same conditionsfor an additional hour. The reaction mixture is then poured over ice,acidified to a pH of 1 by the addition of hydrochloric acid, andextracted several times with methylene chloride. After washing theextract solutions with water, the solvent is driven off by distillationand a residue weighing 8.5 gm. is obtained, which is subjected to theclassic treatment with Girards reactant T. The non-ketone fraction thusobtained, weighing 8 gm. is dissolved in benzene solution and subjectedto chromatography over alumina. Eluting with petroleum ether yieldsa'solidified resin consisting of the 3-rnethyl ether of17a-ethoxymethyl-estradiol (III) which melts at about 45 C. The productis very soluble in alcohol, ether, acetone, benzene and chloroform, andinsoluble in Water.

Anelysis.-C H O molecular weight: 344.48. Calculated: C, 76.70%; H,9.36%. Found: C, 76.5%; H, 9.3%.

The infra-red spectrum confirms the given structure.

Product III is not described in the literature.

Compound III, subjected to the treatment described in Example I(b)yields the aldehyde 17,6-formyl-3-methoxy-A -androstatriene.

EXAMPLE III Preparation of 17 3-f0rmyl-3,B-acetoxy-M-androstene (VII)(a) 5 gm. of brornodimethyl ether in 20 cc. of anhydrous tetrahydrofuranare added slowly to a mixture consisting of 5 gm. of 3B-acetoxy-A-androstene-l7-one (V), 2 gm. of magnesium turnings and 0.5 gm. ofmercuric chloride in 50 cc. of anhydrous tetrahydrofuran. The reactionmixture is maintained under reflux for 1% hours,

then cooled. The magnesium compound formed by the reaction is decomposedwith a 10% aqueous solution of sulfuric acid and extracted withmethylene chloride. The extract solutions are washed with a solution ofsodium bicarbonate and with Water, dried and the solvent is distilledoff. The residue is crystallized from ethanol and then from isopropylether. SB-acetoxy-17fl-hydroxy-17amethoxymethyl-A -androstene (VI)having a melting point of 182 C. and a specific rotation of [oz] =-32(c.=0.5% in chloroform) is obtained.

In addition, the ethanolic mother liquor from the crystallization stepis subjected to chromatography over alumina and after elution with amixture of benzene and ether (2:1), an additional quantity of the sameproduct having a melting point of 182 C. is obtained. For analysis, theproduct is crystallized from isopropyl ether, whereupon a sample meltingat 188 C. and having a specific rotation of [ct] =95 (c.=0. 5% inchloroform) is obtained. This compound is soluble in alcohol, ether,acetone, benzene and chloroform, and insoluble in water and diluteaqueous acids and alkalies.

Analysis.-C H O molecular Weight: 376.52. Calculzged: C, 73.36%; H,9.64%. Found: C, 73.5%; H, 9.6 0.

(b) 300 mgm. of compound V1 is subjected to a treatment analogous tothat described in Example I(b), whereby the corresponding aldehyde, thatis 17fl-formyl- 3B-acetoxy-A -androstene (VII) is obtained. Thesemicarbazone of compound VII melts at about C.

EXAMPLE IV Preparation of 3 ot-acetoxy-20-f0rmyZ-pregnane-1 1 -one (X(a) 625 mgm. of magnesium turnings and 50 mgm. of mercuric chloride areadmixed with 12 cc. of anhydrous tetrahydrofuran, and then 2.5 cc. ofbromodimethyl ether in 12 cc. of tetrahydrofuran are introduced intothis mixture very slowly, while cooling. The mixture is agitated for /2hour, and then 5 gm. of 3a-acetoxypregnane-ll,20-dione in 30 cc. oftetrahydrofuran are added. Agitation is continued for an additional /2hour. Thereafter, the reaction mixture is poured into a solution of 10cc. of 2 N sulfuric acid in 200 cc. of iced water and the mixture isextracted with ether. The organic phase is separated and washed with asaturated solution of sodium bicarbonate and then with water. Afterdrying, the solvent is driven off by distillation, the residue isdissolved in 20 cc. of pyridine, cc. of acetic acid anhydride are addedand the mixture is allowed to stand at room temperature for 2 hours. Theanhydride is bydrolyzed and the mixture is extracted with ether. Theextract solutions are combined and successively washed with dilutehydrochloric acid, water, sodium bicarbonate and Water, then dried andthe solvent is driven off in vacuo. The residue is crystallized frompetroleum ether. 3a-acetoxy-20f-methoxymethyl-20-hydroxy pregnane-llone(IX) having a melting point of 147 C. and a specific rotation of [a]=+6l (c.=0.5% in chloroform) is obtained. An additional quantity of thisproduct can be recovered from the mother liquor. Compound IX is obtainedin the form of colorless crystals which are soluble in alcohol, ether,acetone, benzene, chloroform and isopropyl ether and insoluble in water.

It is not described in the literature.

(b) 1 gm. of compound IX, melting point of 147 C., is dissolved in cc.of phosphorus oxychloride. The solution is agitated for 3 hours atambient temperature, whereby a yellow solution is obtained, which ispoured over ice. The suspension thus obtained is vacuum filtered. Thefilter cake is washed with water and dissolved in methylene chloride.This solution is washed with sodium bicarbonate and Water, dried and thesolvent is driven oif in vacuo. The residue is crystallized from ether,whereby 220 mgrn. of a ZO-isomer of 3a-acetoxy-ZO-formyl-pregnane-ll-one (X) having a melting point of 190 C. and aspecific rotation of [u] =+64 (c.=0.5% in chloroform) are obtained.

Analysis.C H O molecular weight: 388.5. Calculated: C, 74.19%; H, 9.34%.Found: C, 73.9%; H, 9.6%.

The other ZG-isomer is isolated from the filtrate. This isomer has amelting point of 160 C. and a specific rotation of [a] =+75 (c.=0.5% inchloroform).

The two isomers are soluble in alcohol, acetone, benzene, chloroform andhot ether, and insoluble in water and dilute aqueous acetone andalkalies.

It is to be understood that the invention is not limited to the specificembodiments described above. More particularly, the reaction conditions,the reaction temperatures and other conditions may be varied withoutdeparting from the spirit of the invention or the scope of the appendedclaims.

We claim:

1. A process for the preparation of formylated steroids selected fromthe group consisting of 17-formyl andros tanes and ZO-formyl pregnaneswhich comprise the steps of reacting a keto steroid selected from thegroup consisting of 17-keto-androstanes and 20-keto-preguanes with alower alkoxymethyl magnesium halide in the presence of cycloalkyleneether selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, recovering a loweralkoXymethyl-hydroxy steroid, subjecting said loweralkoxyrnethyl-hydroxy-steroid to the action of an acid dehydrating agentselected from the group consisting of oxalic acid and phosphorusoxychloride and recovering said formylated steroids.

2. The process of claim 1 wherein the reaction between said ketosteroids and said lower alkoxymethyl magnesium halide is carried out inthe presence of a halide of a metal selected from a group consisting ofmercury, zinc and cadmium.

3. A process for the preparation of formylated steroids selected fromthe group consisting of 17-formyl androstanes and 20-formyl pregnaneswhich comprise the steps of reacting a keto steroid selected from thegroup consisting of l7-keto-androstanes and ZO-keto-pregnanes with acompound selected from the group consisting of methoxymethyl magnesiumchloride, methoxymethyl magnesium bromide, ethoXymethyl magnesiumchloride and ethoxymethyl magnesium bromide in the presence of a solventselected from the group consisting of tetrahydrofuran, Z-methyltetrahydrofuran and tetrahydropyran, and mercuric chloride, recovering ahydroxy steroid selected from the group consisting of17-hydroxy-l7-methoxymethyl androstanes, 17-hydroxy-l7ethoXymethyl-androstanes, ZO-hydroxy-ZO-ethoxymethyl-pregnanes andZO-hydroxy- 20-methoXymethyl-pregnanes, subjecting said hydroxy steroidto the action of an acid dehydrating agent selected from the groupconsisting of oxalic acid and phosphorus oxychloride and recovering saidformylated steroids.

4. The 3-methyl ether of 17ot-methoxymethy1 estradiol.

5. The B-methyl ether of 17a-ethoxymethyl estradiol.

6. 3 p acetoxy 17B-hydroXy-l7ot methoxymethyl-A androstene.

7. 17fi-formyl-3-methoxy-A -androstatriene.

8. The semicarbazone of 17,8-formyl-3-methoxy- A -androstatriene.

No references cited.

1. A PROCESS FOR THE PREPARATION OF FORMYLATED STEROIDS SELECTED FROMTHE GROUP CONSISTING OF 17-FORMYL ANDROSTANES AND 20-FORMYL PREGNANESWHICH COMPRISE THE STEPS OF REACTING A KETO STEROID SELECTED FROM THEGROUP CONSISTING OF 17-KETO-ANDROSTANES AND 20-KETO-PREGNANES WITH ALOWER ALKOXYMETHYL MAGNESIUM HALIDE IN THE PRESENCE OF CYCLOALKYLENEETHER SELECTED FROM THE GROUP CONSISTING OF TETRAHYDROFURAN, 2-METHYLTETRAHYDROFURAN, AND TETRAHYDROPYAN, RECOVERING A LOWERALKOXYMETHYL-HYDROXY STEROID, SUBJECTING SAID LOWERALKOXYMETHYL-HYDROXY-STEROID TO THE ACTION OF AN ACID DEHYDRATING AGENTSELECTED FROM THE GROUP CONSISTING OF OXALIC ACID AND PHOSPHORUSOXYCHLORIDE AND RECOVERING SAID FORMYLATED STEROIDS.
 7. 17B-FORMYL-3-METHOXY -$1,3,5(10)-ANDROSTATRIENE.